We are applying for continuation of funding for studies of respiratory function and carbon dioxide (CO2) response in patients with panic disorder. A large body of research and clinical experience now indicates that respiratory disturbance, including hyperventilation and exaggerated response to inhaled CO2, is directly involved in the pathophysiology of panic disorder. We have fit this into a theoretical model for panic that involves respiratory hyperactivity, serotonergic hypoactivity, and exaggerated noradrenergic function at the level of the human brainstem. The studies proposed in this application are aimed at the respiratory portion of this theoretical triangle. Interim analysis of data generated during the present funding period confirms our original hypotheses that panic patients have resting respiratory hyperactivity, do not panic to room air hyperventilation, and have both behavioral and biological hypersensitivity to inhaled CO2. We also found that the panic response to 7% CO2 robustly discriminates between panic disorder patients and controls, that changing "instructional set" does not alter panic response to CO2, and that imipramine, but not cognitive/behavioral therapy, decreases CO2 sensitivity. Finally, we successfully developed an ambulatory respiratory monitor that measures both respiratory frequency and tidal volume. In the next funding period we propose to answer four specific questions: 1) does panic to 7% CO2 have diagnostic specificity for panic disorder? 2) do patients with panic disorder have respiratory abnormalities outside of the laboratory and are in vivo panic attacks characterized by acute change in respiratory pattern? 3) can we replicate and extend the preliminary finding that antipanic medication, but not antipanic psychotherapy, decreases CO2 sensitivity? and 4) are there other cognitive manipulations such as creating the illusion of control and basic reassurance that affect panic to CO2?